What is TCR?
T cells are the main functional cells in the acquired immune system, which are responsible for identifying antigens and directing other immune cells to carry out immune responses. T cell antigen receptor on T cell surface plays a key role in antigen recognition. T cells play an important role in the immune system and can attack pathogens and cancer cells. T cell receptor (TCR) can recognize different ligands with wide affinity and participate in activating various physiological processes. TCR cell therapy customizes functional TCR, which has the best antigen recognition characteristics and uses the human immune system to fight cancer.
The structure of TCR
Figure 1. The structure of TCR
T cells are the main components of adaptive immune response. The structure of their antigen recognition receptors has been confirmed. The cloned TCR consists of alpha and beta chains as heterodimers. TCR heterodimers mainly bind to several signal transduction subunits of CD3, CD3gamma, CD3delta and CD3E heterodimers and CD3delta homologous dimers. Different subunits of CD3 contain the activation sequence of tyrosine, the immune receptor, ITAM, but the number of each subunit is different. CD3gamma, CD3delta and CD3epsilon contain one, respectively, while CD3delta contains three tandem ITAMs, so that each T cell receptor can produce 10 ITAMs. Tyrosine phosphorylated ITAM can couple TCR with intracellular signal transduction pathways and recruit SH2 domain proteins, such as tyrosine kinase ZAP70, from TCR. However, there are still two hypotheses to explain why TCR complex contains so many signal transduction subunits and ITAM. One is that CD3 or ITAM alone may perform different signal transduction functions by recruiting unique effector molecules, and the other is that the main function of multiple TAMs is to amplify TCR signals.
TCR signaling pathway
TCR recognizes a peptide that binds to MHC molecules presented by antigen presenting cells (APCs). Single TCR can recognize different ligands (auto-peptide and foreign-peptide) with wide affinity. TCR is involved in triggering different functional outputs. In thymus, the binding intensity of pMHC and TCR signals determines the process of cell development and differentiation. When the binding force is between the minimum and the maximum, it promotes the survival of thymocytes and transforms into the mature stage of CD4*CD8 or CD4CD8*. If the TCR and pMHC are too low or too high, cell apoptosis will occur. Peripherally, the low affinity binding of autologous pMHC to TCR provides the strong survival signal necessary to maintain the initial T cells, and also promotes the full activation of autologous pMHC in high affinity encounters with foreign antigens.
The intensity of TCR signal is crucial for the production of appropriate T cells. TCR signal transduction response guides the successful differentiation of CD4* T cells into different T helper cell subsets, and plays a key role in specific T helper cell subsets. The intensity and duration of TCR cells are related to the differentiation of memory T cells, and are also the basic determinants of T cell impotence or depletion. TCR signal is regulated by biochemical and molecular mechanisms, leading to signal amplification or attenuation. The mechanism of TCR regulation is complex and diverse, but it can be divided into three basic levels: early signal transduction effector molecule; signal molecule development stage; and dynamic regulation of TCR signal intensity.
TCR binds to the MHC complex expressed on antigen presenting cells (APC) to activate TCR signaling pathway. SRC family protein tyrosine kinase LCK binds to the cytoplasmic domain of CD4 and CD8 common receptors, and is recruited to TCR through the co-binding of CD8 or CD4 with MHC or MHC class I complexes, respectively. LCK phosphorylation enables protein tyrosine kinase ZAP70 to bind to the CD3 chain. T cell activation cohesion factor LAT is phosphorylated, activated T cells, recruited multiple cohesion factors and effector molecules, forming LAT signal transducers. Activation of LAT-related effector molecules leads to signal transduction through three main signaling pathways: calmodulin, MAPK and NF-KB signaling pathways. Calmodulin signal transduction activates T cell nuclear factor (NFAT) for nuclear translocation; MAPK signal transduction leads to actin aggregation and activation of transcription factors FOS, JUN, AP-1; and NF-K B signal transduction causes nuclear translocation of REL and NF-K B transcription factors: These transcription factors synergize to cause T cell proliferation, migration, cytokine production and effect function. TCR is also usually associated with the activation of its common receptor CD28 or cytokine receptors (such as PI3K, AKT, PIP3, PTEN, JAK, STAT) and other signaling pathways.
Application of TCR
T cells were modified by TCR gene to exert specific immune regulation or cytotoxic activity. It has great potential in the treatment of malignant tumors and other diseases. Tumor-associated antigen-specific TCR gene was transduced into T lymphocyte for the treatment of tumors, starting with melanoma.
In addition to melanoma, some scholars have recently attempted to extend TCR gene therapy to the treatment of colorectal cancer, synovial cell carcinoma, neuroblastoma, lymphoma and other tumors.
TCR DNA vaccine
TCR gene can be used as a target gene for therapy besides being a guide gene for targeted therapy. In recent years, the use of TCR DNA vaccine to treat some diseases has been gradually carried out. TCR DNA vaccine is a kind of gene vaccine. Through the expression of antigen protein in the body, the body can induce specific immune response, selectively kill pathogenic T cells or inactivate them to play a therapeutic role.
The future of TCR
At present, two research hotspots in the field of TCR gene therapy are: (1) mutation of CDR region to improve the affinity of TCR transduction; (2) pairing of TCR A and beta chains. There are three main problems in TCR gene therapy in the future: (1) in vivo environment of T cells after transfusion; (2) quality problems of T cells after transfusion; (3) safety of transduction of TCR.
In TCR gene therapy, antigen-specific TCR gene modified T cells in tumors and infectious diseases have achieved exciting results, which has proved to be a promising therapeutic strategy. Antigen-specific TCR gene-modified T cells have replaced the traditional effector cells and become the hotspot of this field. Although there is still some distance from large-scale clinical application and becoming a conventional treatment method, it is believed that TCR gene therapy will become more and more perfect and play a greater therapeutic role with the deepening of research.